ORCID Profile
0000-0003-4390-8767
Current Organisation
University of Oxford
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Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2013
Abstract: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status. We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2 95% CI, 0.53 to 2.72 P = .66 P INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87 95% CI, 0.64 to 1.16 P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11 95% CI, 0.001 to 0.832 P = .027 P INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92 95% CI, 0.60 to 1.42 P = .71). Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.
Publisher: Springer Science and Business Media LLC
Date: 30-03-2008
DOI: 10.1038/NG.111
Abstract: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Publisher: Springer Science and Business Media LLC
Date: 14-10-2007
DOI: 10.1038/NG.2007.18
Abstract: To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 in iduals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication s le sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four s le sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).
Publisher: Oxford University Press (OUP)
Date: 27-08-2008
DOI: 10.1093/HMG/DDN267
Abstract: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy in iduals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17 95% confidence interval [CI]: 1.12-1.22 P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19 95% CI: 1.15-1.23 P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2011
DOI: 10.1158/1078-0432.CCR-10-1720
Abstract: Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3% P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same in idual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P & 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. Clin Cancer Res 17(5) 1122–30. ©2011 AACR.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2009
DOI: 10.1038/ONC.2008.361
Abstract: The seminal 'two-hit hypothesis' implicitly assumes that bi-allelic tumour suppressor gene (TSG) mutations cause loss of protein function. All subsequent events in that tumour therefore take place on an essentially null background for that TSG protein. We have shown that the two-hit model requires modification for the APC TSG, because mutant APC proteins probably retain some function and the two hits are co-selected to produce an optimal level of Wnt activation. We wondered whether the optimal Wnt level might change during tumour progression, leading to selection for more than two hits at the APC locus. Comprehensive screening of a panel of colorectal cancer (CRC) cell lines and primary CRCs showed that some had indeed acquired third hits at APC. These third hits were mostly copy number gains or deletions, but could be protein-truncating mutations. Third hits were significantly less common when the second hit at APC had arisen by copy-neutral loss of heterozygosity. Both polyploid and near-diploid CRCs had third hits, and the third hits did not simply arise as a result of acquiring a polyploid karyotype. The third hits affected mRNA and protein levels, with potential functional consequences for Wnt signalling and tumour growth. Although some third hits were probably secondary to genomic instability, others did appear specifically to target APC. Whilst it is generally believed that tumours develop and progress through stepwise accumulation of mutations in different functional pathways, it also seems that repeated targeting of the same pathway and/or gene is selected in some cancers.
Publisher: BMJ
Date: 28-09-2019
DOI: 10.1136/GUTJNL-2019-319126
Abstract: Pathological Wnt pathway activation is a conserved hallmark of colorectal cancer. Wnt-activating mutations can be ided into: i) ligand-independent (LI) alterations in intracellular signal transduction proteins ( Adenomatous polyposis coli , β-catenin), causing constitutive pathway activation and ii) ligand-dependent (LD) mutations affecting the synergistic R-Spondin axis ( RNF43 , RSPO -fusions) acting through lification of endogenous Wnt signal transmembrane transduction. Our aim was to exploit differential Wnt target gene expression to generate a mutation-agnostic biomarker for LD tumours. We undertook harmonised multi-omic analysis of discovery (n=684) and validation cohorts (n=578) of colorectal tumours collated from publicly available data and the Stratification in Colorectal Cancer Consortium. We used mutation data to establish molecular ground truth and sub ide lesions into LI/LD tumour subsets. We contrasted transcriptional, methylation, morphological and clinical characteristics between groups. Wnt disrupting mutations were mutually exclusive. Desmoplastic stromal upregulation of RSPO may compensate for absence of epithelial mutation in a subset of stromal-rich tumours. Key Wnt negative regulator genes were differentially expressed between LD/LI tumours, with targeted hypermethylation of some genes ( AXIN2 , NKD1 ) occurring even in CIMP-negative LD cancers. AXIN2 mRNA expression was used as a discriminatory molecular biomarker to distinguish LD/LI tumours (area under the curve .93). Epigenetic suppression of appropriate Wnt negative feedback loops is selectively advantageous in LD tumours and differential AXIN2 expression in LD/LI lesions can be exploited as a molecular biomarker. Distinguishing between LD/LI tumour types is important patients with LD tumours retain sensitivity to Wnt ligand inhibition and may be stratified at diagnosis to clinical trials of Porcupine inhibitors.
Publisher: Wiley
Date: 25-01-2013
DOI: 10.1002/PATH.4139
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
DOI: 10.1038/AJG.2013.292
Abstract: Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival. We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375). In the VICTOR patients, no specific mutation was associated with DFS, but in idually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021 for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. MSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Cold Spring Harbor Laboratory
Date: 10-01-2023
DOI: 10.1101/2023.01.10.521547
Abstract: An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumours is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identify complement receptor C5aR1 as a druggable target which when inhibited improves radiotherapy even in tumours displaying immunosuppressive features and poor CD8+ T-cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we find that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumour-cell specific functions. C5aR1 targeting results in increased NF-κB-dependent apoptosis specifically in tumours and not normal tissues indicating that in malignant cells, C5aR1 primarily regulates cell fate. Collectively, these data reveal that increased complement gene expression is part of the stress response mounted by irradiated tumours and that targeting C5aR1 can improve radiotherapy even in tumours displaying immunosuppressive features.
Publisher: American Society for Clinical Investigation
Date: 12-10-2023
DOI: 10.1172/JCI168277
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2503
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Enric Domingo.